title: The cytotoxicity and microdosimetry of astatine-211-labeled chimeric monoclonal antibodies in human glioma and melanoma cells in vitro.
abstract: The cytotoxicity of alpha-particle-emitting endoradiotherapeutic compounds is of increasing interest because clinical evaluation of these potential therapeutic agents is commencing. Astatine-211 is a radionuclide with a 7.2-h half-life that emits 5.87 and 7.45 MeV alpha particles. In the present work, we have investigated the in vitro cytotoxicity of 211At-labeled chimeric monoclonal antibodies (mAbs) in monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. The mAbs studied were 81C6, reactive with the extracellular matrix antigen tenascin, Mel-14, directed against the cell membrane antigen proteoglycan chondroitin sulfate, and a nonspecific control mAb, TPS3.2. Cell uptake increased as a function of activity concentration after a 1-h exposure to the 211At-labeled mAbs. The retention of activity was also measured to calculate cumulative activity associated with the cells and the medium. The clonogenic survival as a function of activity concentration was linear in all cases with no detectable shoulder. Microdosimetric analyses were performed based on measured cell geometry, cumulative activity and Monte Carlo transport of alpha particles. Using 18 kBq/ml activity concentration and 1 h of incubation, a two to five times higher activity bound to the microcolonies was found for the specific mAbs compared to the nonspecific mAb. These calculations indicated that a survival fraction of 0.37 was achieved with 0.24-0.28 Gy for D-247 MG cells and 0.27-0.29 Gy for SK-MEL-28 cells. The microdosimetric cell sensitivity, z0, for D-247 MG cells was significantly lower than for SK-MEL-28 cells (0.08 compared to 0.15 Gy). For both cell lines, reduction in survival to 0.37 required an average of only 1-2 alpha-particle hits to the cell nucleus.
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Larsen
authors.forename: G
authors.initials: G
authors.lastname: Akabani
authors.forename: P
authors.initials: P
authors.lastname: Welsh
authors.forename: M R
authors.initials: MR
authors.lastname: Zalutsky
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001246:Astatine / Q000627:therapeutic use*; D004306:Dose-Response Relationship, Immunologic; D004307:Dose-Response Relationship, Radiation; D005910:Glioma / Q000532:radiotherapy*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008545:Melanoma / Q000532:radiotherapy*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D001246:Astatine